Lithium efflux from erythrocytes of normal and manic-depressive subjects has been measured in vitro. The efflux rate constant is substantially repressed during chronic administration of lithium carbonate to most patients. The repression has been found to be reversible within days to weeks after cessation of lithium carbonate ingestion. The mechanism of repression of lithium efflux is presently under investigation at the molecular level. Recent experiments with inhibitors of the erythrocyte calcium pump have shown that these substances produce a substantial inhibition of lithium efflux as well. Activators of lithium efflux has been shown to occur with activators of 2,3-diphosphoglycerate phosphatase, and the same substances also activate calcium ATPase isolated as erythrocyte membrane fragments. These recent observations on the relation between inhibitors and activators of lithium transport and calcium ATPase will be utilized as probes to obtain a detailed view of the mechanism of lithium transport, and will be further applied to the investigation of the normal physiological controls which are altered when the lithium efflux rate constant is repressed as a consequence of lithium carbonate ingestion.